II. PRESENTACIÓN Y ANÁLISIS DE RESULTADOS
6. Sindicato de Armadores y Propietarios de embarcaciones Artesanales
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Here, we studied for the first time the miRNAs expression signature of BL subtypes compared with normal B lymphocytes obtained from reactive lymph nodes of cancer free patients. First, we showed that BL is a distinct entity, supporting the current WHO classification. In fact, we showed that the miRNAs profile of all BL subtypes is quite homogeneous and distinct from those of cancer free lymph nodes. In addition, significantly, we showed that the described BL microRNAs signature is not related to EBV infection. Moreover, we are reporting that miR-221 and miR-222 are significantly down-regulated in BL when compared to healthy (cancer free) controls. These new findings may highlight a different role of these miRNA in lymphoma cells compared to their well-known pro-tumorigenic function in epithelial tumors. To better investigate the potential role of miR-221 and miR-222 in Burkitt pathogenesis, we also analyzed their expression levels in Eµ-Myc transgenic mouse model that resembles an aggressive Burkitt pathogenesis at 6/8 months of life. By analyzing CD- 19+ B cells from the spleen of Eµ-Myc transgenic mice and litter mate WT we found that miR- 221 and miR-222 levels show a severe down-regulation. This common pattern between human and mice suggests that miR-221 and miR-222 are involved in BL pathogenesis. In agree with these results, mir-221 and miR-222 ectopic re-expression in BL cell line (Bjab) reveals interesting new cellular pathways that could be regulated by this class of miRNAs in lymphoma cells. Also, comparing this gene expression profile with a gene expression profile obtained from the mouse model we were able to find a common target that could be considered to play a role in the BL pathogenesis. Thus, further studies, such as western blot analysis in BL cell lines, qRT-PCR and western blot analyses in mouse samples, need to be assessed to validate this protein as a target of the cluster 221/222.
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Our preliminary data on the in vivo mouse model obtained by mating miR-221/222 KO with EµMyc tg mice support our results previously reported: the knockout mouse for miR- 221/222 doesn’t show any particular phenotype but when we cross the miR-221/222 KO with the well-known in vivo model for BL we observe an anticipation of the disease appearance of at least 60 days compared to the wt 221/222-EµMyc tg, indicating that the translocation of Myc needs also the dysregulation of the miR-221 and miR-222 to develop the malignancy. Unfortunately the number of mice is not enough for statistical analysis so we are increasing the litters and furthers studies need to be carry out to establish this KO/tg mouse model as a good in vivo BL model.
Our findings indicate that miR-221/222 can be critical mediators for BL pathogenesis and together with other important genetics alteration such as translocation of Myc can lead to the aggressive phenotype that this B cell malignancy usually shows. These results highlight the potential role of this cluster of microRNAs to be a good tool of diagnosis and prognosis for BL.
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Oncogenic role of miR-483-3p at the IGF2/483 locus.
Veronese A, Lupini L, Consiglio J, Visone R, Ferracin M, Fornari F, Zanesi N, Alder H, D'Elia G, Gramantieri L, Bolondi L, Lanza G, Querzoli P, Angioni A, Croce CM, Negrini M.
Cancer Res. 2010 Apr 15;70(8):3140-9. doi: 10.1158/0008-5472.CAN-09-4456. Epub 2010 Apr 13.
Mutated beta-catenin evades a microRNA-dependent regulatory loop.
Veronese A, Visone R, Consiglio J, Acunzo M, Lupini L, Kim T, Ferracin M, Lovat F, Miotto E, Balatti V, D'Abundo L, Gramantieri L, Bolondi L, Pekarsky Y, Perrotti D, Negrini M, Croce CM.
Proc Natl Acad Sci U S A. 2011 Mar 22;108(12):4840-5. doi: 10.1073/pnas.1101734108. Epub 2011 Mar 7.
In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation.
Pichiorri F, Palmieri D, De Luca L, Consiglio J, You J, Rocci A, Talabere T, Piovan C, Lagana A, Cascione L, Guan J, Gasparini P, Balatti V, Nuovo G, Coppola V, Hofmeister CC, Marcucci G, Byrd JC, Volinia S, Shapiro CL, Freitas MA, Croce CM.
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